Method to reduce damage caused by irradiation of halogenated polymers

ABSTRACT

A method for producing a polymeric film resistant to degradation during sterilization such as gamma irradiation is presented. The method includes the steps of minimizing the number of free radicals formed during sterilization through use of an inert gas and a reactant scavenger within a sterilization pouch, which reactant scavenger may be acid adsorbents which scavenge the acid by-products formed during irradiation. The films retain physical and mechanical properties with long-term storage. The films are particularly amenable for use as packaging laminates in pharmaceutical, food, semiconductor and medical device industries.

FIELD OF THE INVENTION

[0001] The invention relates to the field of packaging and specificallyto reducing damage to package materials caused by radiation tosterilize.

BACKGROUND OF THE INVENTION

[0002] The environmental conditions under which irradiation of polymericdevices and packaging films is conducted can significantly affect theproperties of the polymer. Such irradiation of the polymers could beemployed for sterilization, as is common in the medical andpharmaceutical industry, as well as for structural modification ofpolymer such as cross-linking. The presence of oxygen or air duringirradiation may produce free radicals; radiation may also break bondsgenerating new reactive species such as HF, HCl, F⁻, Cl⁻ from thepolymer constituents. The effect of these radicals depends on the natureof the irradiated polymer, the presence of additives, and otherparameters such as temperature, total dose, dose rate, and duration ofthe exposure of the reactive species. The term reactive species is usedto indicate both the free radicals as well as other reactive speciesformed due to the effects of irradiation. These reactive species cancause chain scission reactions, in which the long backbone chains aswell as side chains are cut, resulting in a loss of the molecular weightof the polymer along with changes to its structural properties. From aproduct use standpoint, the loss of desirable mechanical properties isone of the most important characteristics affected by irradiation ofpolymers. In the case of chlorofluoropolymers such as PCTFE used inpackaging and barrier films, the release of byproducts such as lowlevels of HF, HCl and possibly other organic chlorofluorocarbons is alsoa matter of concern because they react with and have adverse effects onthe barrier and structural properties of the packaging components aswell as the packaged product itself.

[0003] To avoid oxidation, manufacturers generally avoid packagingcomponents under atmospheric conditions, which was common practice inthe past. An alternative is to package the component in foil, pull avacuum on it or introduce a nitrogen/argon flush before irradiationsterilization. This eliminates most of the oxygen thereby reducingoxidation of the polymer during storage. Neither procedure completelysolves the problem of reactive species generated by the effect ofradiation on the polymers. These species can persist for years and reactwith the polymer and components thereof and packaged products duringstorage. This invention describes a process that reduces the oxidationand degradative reactions by scavenging the reactive species that areformed during irradiation and providing a relatively inert storagecondition during post irradiation shelf life.

SUMMARY OF THE INVENTION

[0004] Irradiated polymeric components and methods of producing such aredisclosed and described. A component which is comprised of a polymer isplaced in a tight sealed container. The container also holds a chemicalcompound which acts as a scavenger for the reactive species generatedduring irradiation. Oxygen is removed from the container (e.g. byvacuum) and/or the container may be flushed with an inert gas. Thecomponent in the container is irradiated with a sufficient amount ofradiation so as to sterilize, or accomplish any other desired processsuch as cross linking of the component and sterilize the inside of thecontainer in which it is held. The vacuum and/or inert gas decreasesoxidation of the component and the scavenger reduces reactions with thepolymer thereby increasing the shelf life of the component. While theinvention is described in detail in terms of sterilization usingradiation, the invention may be practiced to draw advantages whereradiation may be used for other applications such as cross linking ofpolymers. Furthermore, although the description refers to the usescavengers for reactive species such as HF and HCl, this invention maybe practiced using scavengers for other reactive species formed duringirradiation. Those familiar with the art of effects of radiation onpolymers may identify the reactive species formed in their particularapplication and practice this invention with the use of appropriatescavengers.

[0005] The sterilized packaged components of the invention may be anycomponent material comprised of a polymer. Examples of polymericmaterials used for making the component are provided herein. Thecomponent may itself be a packaging material such as a component of adrug containing package which has strict sterilization requirements. Thecomponent may be contained within a sealed polymeric bag or outerpackage which bag or outer package is filled with an inert gas andcontains the scavenger material. That bag may be contained within asecond bag or container which is also sealed and filled with an inertgas. Additional bags or outer containers filled with inert gas andpotentially containing a scavenger material may also be used.

[0006] An aspect of the invention is a polymer material componentsterilized with radiation inside of a sealed container which sealedcontainer also holds a hydrogen fluoride and/or hydrogen chloridescavenger.

[0007] Another aspect of the invention is that the polymer material isless subject to deterioration over time due to the inert storageenvironment created by the presence of the scavenger material.

[0008] Yet another aspect of the invention is a method whereby a polymermaterial is irradiated inside of a sealed container which has depletedoxygen content due to the use of vacuum and/or infusion of inert gaswith the sealed container also holding a hydrogen fluoride and/orhydrogen chloride scavenger.

[0009] These and other objects, advantages, and features of theinvention will become apparent to those persons skilled in the art uponreading the details of the sterilized component and method for makingsuch as more fully described below.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010]FIG. 1 is a schematic, perspective view of packaged polymercomponents having packets of reactant scavenger attached to theirsurface.

DETAILED DESCRIPTION OF THE INVENTION

[0011] Before the present sterilized packaged component and method formaking such are described, it is to be understood that this invention isnot limited to particular component or method described, as such may, ofcourse, vary. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments only, andis not intended to be limiting, since the scope of the present inventionwill be limited only by the appended claims.

[0012] Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimits of that range is also specifically disclosed. Each smaller rangebetween any stated value or intervening value in a stated range and anyother stated or intervening value in that stated range is encompassedwithin the invention. The upper and lower limits of these smaller rangesmay independently be included or excluded in the range, and each rangewhere either, neither or both limits are included in the smaller rangesis also encompassed within the invention, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the invention.

[0013] Unless defined otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention belongs. Although any methodsand materials similar or equivalent to those described herein can beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

[0014] It must be noted that as used herein and in the appended claims,the singular forms “a”, “an”, and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a polymeric component” includes a plurality of such components andreference to “the polymer” includes reference to one or more polymersand equivalents thereof known to those skilled in the art, and so forth.

[0015] The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

Invention In General

[0016] In a number of different industries including pharmaceuticals,food, semiconductors, and medical devices, various components are madeof polymeric materials and those materials must be in a sterile formwhen used by a patient. For example, the pharmaceutical industry oftenuses polymeric materials to produce containers for drugs which drugs maybe in any form including liquid, powder and tablet form. All types offoods may be present within containers and semiconductor components usedin the production of computers and related electronic devices are oftenincluded within sealed, sterilized containers. Medical devicesthemselves such as implants and catheters may be comprised of polymericmaterials and the polymers may be composed of polymeric subcomponentse.g laminates In all of these cases it may be essential that thepolymeric component be sterilized prior to use. The sterilizationprocess can be carried out in a number of different ways but is oftencarried out using some form of directed artificial radiation such asgamma radiation which is applied for a period of time and in sufficientamounts so as to render microorganisms non-viable e.g. kill bacteria.

[0017] After the polymeric component is produced the sterilization withirradiation may be carried out in a surrounding atmosphere whichminimizes the adverse effects of reactants such as oxidation. Forexample, the polymeric component may be subjected to radiation in areduced atmosphere environment and/or an environment which has beenflushed with an inert gas in order to remove as much oxygen as possible.However, even when substantially all of the oxygen is removed theradiation may create other reactants such as acids which react with thepolymeric material over time. The reactants produced can adverselyeffect the properties of the materials such as having adverse effects ofthe structural integrity of the polymeric component or subcompoentsthereof. This is particularly undesirable when the sterilized polymericcomponent must be stored for relatively long periods of time prior touse. The present invention endeavors to substantially reduce the adverseeffects of reactants created during the sterilization process.

[0018] The polymeric material may be placed in a reduced atmosphereenvironment and/or surrounded with inert gas for sterilization. Thesterilization may be carried out in a conventional manner such as bysubjecting the polymeric material to radiation with gamma rays. However,in accordance with the present invention the polymeric material ispreferably irradiated inside of a sealed container. The container ispreferably comprised of a material which is permeable to the radiationbut impermeable with respect to oxygen from the outside and bacteria andthe inert gas inside the container and which might recontaminate thepolymeric component. In accordance with the invention the surroundingsealed container also includes a reactant scavenger which scavenger maybe present on the surface of the polymeric component. The reactantscavenger may be any type of absorbent material such as aluminum oxide,sodium oxide, silicon dioxide and ferric oxide. Specific examples ofsuch reactant scavengers and commercially available materials which canact as such reactant scavengers are disclosed here. Other materialswhich decrease the reactivity of compounds such as acids or bases withthe polymer being protected will be known to those skilled in the artreading this disclosure and/or may later be developed.

[0019] The present invention involves both a method for sterilizing andstoring a polymeric material and the packaged sterilized polymericmaterial obtained in accordance with that method. The method stepsinvolve sealing a polymeric component inside a container which containeralso holds and inert gas and a reactant scavenger. The container holdingthe polymeric component is then subjected to sufficient amounts ofradiation such as gamma radiation in order to render microorganisms suchas bacteria contained within the container non-viable. The componentwithin the container may then be stored for relatively long periods oftime where the reactant scavenger is allowed to come into contact withreactants which may have been created on the surface of the polymericcomponent by the radiation or diffuse out from the bulk of the polymericcomponent.

[0020] The product of the invention is thus a packaged, sterilizedpolymeric component. The packaged component includes the polymericcomponent which is preferably surrounded by an inert gas and in thepresence of a reactant scavenger which is preferably on the surface ofthe polymeric component. The polymeric component inert gas and reactantscavenger are all sealed within the container which container isimpermeable to bacteria and the inert gas.

[0021] The reactant scavenger must, at some point, come into contactwith the reactants in order to decrease their reactivity. This can becarried out in a number of different ways. For example, the reactantscavenger can be placed inside of packages which are comprised of gasimpermeable walls, e.g. Tyvek™ material may be used to create containersin which components being sterilized are placed. The reactant scavengermay be placed on the surface of the polymeric component, may be embeddedinto the polymeric component or may be embedded into or onto the surfaceof the packaging material. In addition, the surface of the polymericcomponent being sterilized may be chemically treated so that it binds tothe reactant scavenger. Any and all of these methods may be used aloneor in combination with different types of reactant scavengers indifferent combinations.

[0022] The reactant scavengers may be antioxidants or oxygen absorbentswhich include Freshpax™ manufactured by Multisorb Technologies, NY;Mitsubishi Ageless™ Oxygen Adsorbents, manufactured in Ontario, Canada;Hydrogen fluoride adsorbents include Activated Alumina such as A-202HF™manufactured by UOP, Des Plaines, Ill.; DD-450™ manufactured by AlcoaWorld Chemicals; HF-200™ manufactured by Alcoa World Chemicals;Florocel™, Activated Alumina manufactured by Lawrence Industries in theUnited Kingdom; Fluorocel 830™, Porocel manufactured in Little Rock,Ark.; Actiguard HF™ manufactured by Alcan Chemicals, TX.

[0023] Hydrogen Chloride adsorbents of various types are alsocommercially available and known to those skilled in the art. Forexample, it is possible to use Activated Alumina 9139ATM manufactured byUOP, Des Plaines, Ill.; CL-750™ manufactured by Alcoa World Chemicals;Selexsorb® HCl manufactured by Alcoa World Chemicals; Actiguard™ Clmanufactured by Alcan Chemicals, TX.

[0024] Those skilled in the art will recognize the amounts of thedifferent reactant scavengers which would be used based on the type ofradiation, amount of radiation and polymer material being used. Theamounts being used can be calculated based on the absorbent ability ofthe reaction scavenger being used and amount of reactant that would beexpected to be generated.

[0025] With respect to hydrogen fluoride and hydrogen chloridescavengers it is possible to use 80 to 100 grams of the scavengers per800 to 1200 feet of irradiated film (7-10 mil (thick)). For mostcommercially available catalyst, preferred loading of reactive speciessuch as chloride and fluoride to volume of fresh catalyst is in therange of about 30-50 lbs/cubic feet.

[0026] With respect to oxygen scavengers there are commerciallyavailable oxygen scavengers which have known absorbent capacity. Thevolume of the sterilization chamber is known or can be calculated.Accordingly, the amount of the absorbents (reactant scavengers) can bereadily determined. The calculation can be readily worked out by thoseskilled in the art knowing the chemical structure of the polymericmaterial and packaging materials used. The present invention can becarried out with greatly different amounts of reactant scavengers andobtain a desired result. However, in order to not waste product in termsof the amount of reactant scavengers and in order to have someassurances that all the reactants are being effected it is desirable tocarry out some calculations. However, if too much or too little of thereactant species is included the invention remains useful.

[0027] It is pointed out that in a given application there areapproximately 4 liters of air or 800 ml of oxygen in the container whichbecome exposed to gamma radiation. Using oxygen scavengers with knownabsorbent capacities of about 1000 ml would result in the removal of allof the free oxygen present in the “headspace” of the container. Thisprocess could be performed in 1 to 2 days before exposure to radiationto ensure removal of all of the oxygen.

Definitions

[0028] The term “polymeric component” is used herein to describe any ofa variety of types of polymer materials including polyolefins,polyvinyls, polyethers, polyesters, polyamides, polyurethanes and thelike which may be used alone or in various combinations to create acomponent which can be molded into a structural form. Examples ofpolymeric components include, but are not limited to, containers fordrugs, drug delivery device components, food containers, containers forsemi-conductor components, medical device implants, and containers formedical devices. The polymeric material may be any type of polymer andis preferably a polymer which when subjected to a sterilizationprocedure such as sterilizing radiation generates a reactant such as anacid (e.g. HCL, and HF). The polymeric component may be and preferablyis present in multiple copies so that several polymeric componentsincluding 10's or even 100's or 1000's of polymeric components may bepresent within the surrounding sealed container. The polymericcomponents are stored in the sealed container until they are introducedinto a manufacturing process and/or are used directly by the patient.

[0029] The terms “irradiating” and “subjecting to radiation” and thelike are used interchangeably herein and are intended to mean the use ofman-made or artificial radiation such as gamma radiation, X-rayradiation, electron beam radiation and the like used for sufficientperiods of time and/or in sufficient amounts so as to rendermicroorganisms such as bacteria, parasites, viruses and fungusnon-viable.

[0030] Irradiation is preferably used in the invention in order to carryout sterilization. The sterilization process preferably destroys alltypes of pathogens, e.g. microorganisms, bacteria, virus, and infectiousproteins which might be present on the component being irradiated. Theradiation may be any type of electromagnetic radiation which is anartificially generated radiation (not merely naturally occurringradiation from the sun or surrounding environment) and may beelectromagnetic radiation such as UV, visible light, X-rays, Gamma rays,and electron beam radiation. Those skilled in the art will recognizevarious types and combinations of radiation which may be effectivelyused in order to carry out the desired sterilization process. Thescavenger used may be any substance that can absorb or sequester anotherundesirable chemical species. The reactant species may be any speciesthat by virtue of its chemical nature will react with other materialsthat it comes into contact with. Such species may be formed by theeffect of the radiation or by the effective other chemical species onthe material.

[0031] The methodology of the invention whereby a component isirradiated is preferably carried out in a vacuum or more specifically areduced atmosphere environment. The vacuum may be created by physicalmeans or by the use of a chemical oxygen absorbent. The environment maybe subjected to vacuum and then filled with inert gas such as nitrogenor argon gas. Vacuum pumps can be used to create a vacuum in the rangeof 100 to 0.001 mTorr. The object of producing the vacuum and providingthe inert gas is to remove as much reactive species such as oxygen gasfrom the environment as possible with consideration to practicalitiesand economic concerns.

Polymeric Materials

[0032] Those skilled in the art will recognize that a wide range ofdifferent polymeric materials can be used in producing the polymericcomponents and packaging materials to be treated in connection with thepresent invention. However, to provide further guidance the followinglist of materials is provided below. Species Commercial GeneratedPolymer name by irradiation Commercial Product PCTFE Aclar ® F⁻, Cl⁻, O*O₂: FreshPax, Ageless Neoflon ® F⁻: Kel-F ® A-202HF, DD-450, HF-200,Chemfluor ® Florocel, Fluorocel 830. Tecafluon Actiguard HF Voltalef ® ™Cl⁻: 302 9139A, CL-750, Selexsorb ® VapoShield ™ HCl, Actiguard Cl ECTFEHalar ™ F⁻, Cl⁻, O* O₂: FreshPax, Ageless Dyneon ™ F⁻: A-202HF, DD-450,HF-200, Florocel, Fluorocel 830. Actiguard HF Cl⁻: 9139A, CL-750,Selexsorb ® HCl, Actiguard Cl PVC Geon ® Cl⁻, O* O₂: FreshPax, AgelessViclon ® Cl⁻: Benvic ® 9139A, CL-750, Selexsorb ® HCl, Actiguard Cl PVDCSaran ® Cl⁻, O* O₂: FreshPax, Ageless Cl⁻: 9139A, CL-750, Selexsorb ®HCl, Actiguard Cl

[0033] The term “reactant scavenger” is used herein to describe anymaterial which reduces the reactivity of another component. Examplesinclude oxygen absorbents and acid absorbents. Materials which preventor reduce oxidation as well as prevent or reduce the effects of acidsuch as hydrogen chloride on the polymer are considered reactantscavengers.

[0034] The reactant scavengers are more generally defined above.However, to provide guidance to those skilled in the art examples ofsome useful reactant scavengers are provided below.

[0035] Oxygen Adsorbents:

[0036] 1. Freshpax, Manufacturer: Multisorb Technologies, NY

[0037] 2. Mitsubishi Ageless Oxygen Adsorbents, Ont., Canada

[0038] HF Adsorbents:

[0039] 1. Activated Alumina A-202HF. UOP, Des Plaines, Ill.

[0040] 2. DD-450. Alcoa World Chemicals.

[0041] 3. HF-200. Alcoa World Chemicals.

[0042] 4. Florocel, Activated Alumina. Lawrence Industries, UK

[0043] 5. Fluorocel 830, Porocel, Little Rock, Ark.

[0044] 6. Actiguard HF. Alcan Chemicals, TX

[0045] HCl Adsorbents:

[0046] 1. Activated Alumina 9139A. UOP, Des Plaines, Ill.

[0047] 2. CL-750. Alcoa World Chemicals.

[0048] 3. Selexsorb® HCl Alcoa World Chemicals.

[0049] 4. Actiguard Cl. Alcan Chemicals, TX

[0050] This invention describes an active packaging process to reducethe loss of physical properties of film laminates used inpharmaceutical, food, semiconductor and medical device packaging. Anexample of such a polymer film and its laminates are Aclam (Honeywell).Where the primary barrier film in the laminate is Aclar and the food,drug-contacting surface may be an olefin such as PE, PP, EMA, EVA orEAA. The packaging film could be formed using lamination adhesives.

[0051] It has been observed that sterilization of these materials usinggamma or electron beam irradiation reduces physical properties such aspeel strength of laminates, toughness, delamination frequency of blisterpackages and the post sterilization shelf life has a direct bearing onthe results. As the films were kept in their sterilization containersbeyond the first few weeks the peel strength of the laminates continuedto reduce with time. Investigations have shown that irradiation of thelaminates in these conditions releases HF, HCl and possibly otherorganic chlorofluorocarbons. These reactive species appear to play amajor role in degradation of the laminate properties as long as the filmis stored inside the original container. From a bioburden viewpoint itis not practical to remove the materials from the containers if thematerial is not scheduled for immediate use. It is conceivable that an“inert” process should allow the laminate to have a longer practicalshelf life without a significant loss of physical properties.

[0052] It was discovered that a two-pronged approach can be used tosolve this problem;

[0053] 1. First an inert environment was created to reduce the number offree radicals formed during gamma irradiation of this material. This wasdone by sealing the sterilization pouches that contain rolls of laminatefilm (multiple interconnected polymeric components) under a nitrogenflush and/or by adding oxygen-adsorbing packets (Freshpax, MultisorbCorp, NY) with a known capacity for adsorbing oxygen.

[0054] 2. HF and HCl adsorbents (A-202HF & 9139A UOP, IL) were added tothe sterilization pouch to scavenge the reactive species (F⁻ & Cl⁻) thatare formed inside the package post-irradiation of thepolychlorotrifluoropolymer, Aclar.

[0055] The results of the investigation showed that the laminate filmirradiated using gamma to 25-40 kGy using the inert process exhibited asignificantly less drop in peel strength as compared to the control(film irradiated in air). While the peel strength of the control droppedsignificantly beyond a post gamma shelf life of 3 weeks, no suchreduction was seen in the “inert” group up to 12 weeks of post gammashelf life. Other tests such as rupture and delamination frequency ofblisters formed using these materials also confirmed the findings of thestudy. The findings could be summarized as follows:

[0056] 1. Inert environment reduces impact of gamma irradiation withoutaffecting sterility of product.

[0057] 2. HF/HCl scavengers effectively reduced damage caused insidesealed sterilization pouches.

[0058] 3. The overall result is reduced loss of desirable properties andsignificant increase in shelf life.

[0059] Definition of Problem:

[0060] Radiation sterilization of polymer-based materials causeschemical changes in the polymer that are accompanied by immediatechanges in physical properties such as embrittlement and/or stiffeningand discoloration in many instances. Peroxides are formed that breakdown with time and thus the polymer continues to change its propertiesduring its shelf life, long after radiation has ceased.

[0061] Those skilled in the art will recognize that it is important tomaintain desirable physical properties with respect to materials andpackaging being irradiated. Those properties include properties such asthe tensile strength, ultimate elongation, toughness, modulus, and peelstrength of laminates. In addition, characteristics such as odor,discoloration and corrosion or materials need to be taken intoconsideration when carrying out the processing of the present invention.It is preferable to minimize changes in these characteristics. Ifchanges in some or all of these characteristics change too much thecomponent will not be useful. However, changes of ±25% or less,preferably ±10% or less or more preferably ±5% or less may be caused bythe sterilization and storage procedures that may be used with theinvention. The reduction in changes may be over long periods, e.g. 3days or more, 7 days or more, 30 days or more or 1 year or more.

[0062] The plastic composition used in such containers typicallyincludes a plastic resin that is suitable for contact with blood, suchas polyvinyl chloride, polyolefin or polyester. The plastic compositionmay also include additives, for example, to stabilize the plasticcomposition during processing or during sterilization of the container,which may, at times, be carried out at high temperatures.

[0063] Unfortunately, exposure of certain plastic compositions to hightemperatures, such as during extrusion of the plastic composition and/orduring steam sterilization, may occasionally cause degradation of theplastic composition. Degradation, which is believed to be associatedwith a molecular breakdown of the polymer resins and other materials,may result in a weakening of the overall mechanical strength of thecontainer. More particularly, degradation may result in a weakening ofthe peripheral seals and a reduction in the impact strength (i.e.ability of the container to withstand impact). Moreover, exposure toheat and/or even extended exposure to less severe environments may alsocause undesirable and aesthetically unacceptable discoloration (e.g.yellowing) of the plastic material.

[0064] To prevent or reduce degradation and/or discoloration, inclusionof a small amount of certain additives can help stabilize the plasticmaterial during high temperature heating and during exposure to certainother environments. As reported in U.S. Pat. No. 4,280,497, which isincorporated by reference herein, epoxodized oils, such as epodixidizedsoy been oil and epoxodized linseed oil may be used as heat stabilizers.Also, as reported in Laermer et al. “Use of Biological Antioxidants asPropylene stabilizers”, Plastics and Rubber Processing and Applicants 14(1990) 235-239 and Laermer et al. “Alpha-Tocopherol (Vitamin E)—TheNatural Antioxidant for Polyolefins” Journal of Plastic Film andSheeting, Vol. 8, July 1992 (both of which are also incorporated byreference), Vitamin E (which is a mixture of tocopherols andtocotrienols) is an antioxidant that can serve as a stabilizer duringextrusion of polyolefins. Vitamin E as an antioxidant is preferredbecause, as reported in the 1992 article by Laermer, it is non-toxic andis “generally regarded as safe” (GRAS) by the FDA.

[0065] For example, the present invention is directed, in part, to aplastic or polymeric composition that includes a plastic resin, VitaminE and plasticizer. In one aspect of the present invention, the plasticor polymeric resin may be polyvinyl chloride (“PVC”), while in anotheraspect of the present invention, the plastic resin may be a non-PVC suchas polyolefin. (6,468,258 Plastic compositions including vitamin E formedical containers and methods for providing such compositions andcontainers)

[0066] In an effort to determine the cause of accelerated wear rates andpremature component failures, studies have been conducted on materialvariables involved in component fabrication and utilization. Deformationand loosening of implants bought on by excessive wear rates has beencorrelated to .gamma.-irradiation sterilization in air causing chainscission, which lowers the wear resistance and accelerates thedegradation process.

[0067] Sterilization by .gamma.-irradiation has been the method ofchoice for implants since about 1980. However, .gamma.-sterilizationgenerates free radicals, which react in the presence of oxygen to almostexclusively form peroxyl radicals.

[0068] These free radicals and peroxyl radicals react with PE chains andeach other to form oxidative degradation products and additional radicalspecies. This cycle of oxidation product and radical species formationhas been shown to occur over several years as oxidation levelscontinuously increase in components over this time period. The resultingformation of chain scission products creates shorter molecular chains,degrading the mechanical properties and performance of UHMWPE implants.Furthermore, the damage caused by .gamma.-irradiation does not requirethe implant to be exposed to levels of stress found in use. Instead,oxidative degradation of gamma.-irradiated components may occur duringstorage prior to implantation.

[0069] In U.S. Pat. No. 5,827,904 a composition for the manufacture ofmedical implants is shown, which consists of a polymeric material inpowder form and a carotenoid doped into the polymer to produce aoxidation-resistant matrix for forming the implant. In the dopingprocess the carotenoid is dissolved solved in an organic solvent, suchas 2-propanol, cyclohexane, n-hexane, benzene, and the like.

[0070] The object of the present invention is to provide an improvedmethod for the addition of an antioxidant to UHMWPE in order to obtain ahomogenous mixture of ultra high molecular weight polyethylene and anantioxidant.

[0071] The purpose of adding an antioxidant to UHMWPE is to reduceoxidation of the polymer during sterilization and post sterilization andthereby decrease the wear of the implant in the body. Sterilization with.gamma.-radiation induces free radicals in the material and theseradicals react with oxygen to produce peroxy radicals which attack thepolymer chains. Chain scission drastically reduce the wear resistance ofthe polymer, for example, by lowering the molecular weight. Naturalantioxidants can react with radiation induced free radicals in thepolymer thereby terminating the chain scission process and in this wayreduce the oxidation of the polymer. Examples of antioxidants which canbe used in the method according to the invention include alpha.- and.delta.-tocopherol; propyl, octyl, or dodecyl gallates; lactic, citric,and tartaric acids and their salts; as well as orthophosphates. A usefulantioxidant may be vitamin E.

[0072] UHMWPE doped with an antioxidant by the method of the inventionhas excellent properties for the manufacturing of implants, especiallyjoint prostheses. The UHMWPE powder doped with antioxidant iscompression molded either directly into implants or into blocks, fromwhich implants are produced by mechanical processing, e g turning, etc.Finally, the implant having excellent wear resistance and markedlyreduced degradation in the body are packaged and sterilized.

[0073] In order to further improve the wear resistance of UHMWPE or theimplants, the antioxidant doped UHMWPE material may be subjected togamma.- or .beta.-radiation at a dose above 2 Mrad, preferably above 9Mrad, followed by annealing (remelting), i e subjecting the UHMWPEparticles or the implant to an elevated temperature, preferably above80° C. when vitamin E is used. This procedure results in an increasedcrosslinking of the polymer, thereby enhancing the wear resistancethereof. This radiation/remelting treatment can be carried out at anystage in the manufacturing process; from powder to implant.

Reactant Scavengers

[0074] A wide range of different materials may be used for their effecton reducing oxidation and/or reactions with various acids created duringthe sterilization process. However, it is believed that there are anumber of commercially available materials which could be readilyincluded within the sealed container holding the polymeric component.Some examples of these materials which would be considered to bereactant scavengers are provided below.

[0075] The following reactant scavengers are specifically useful ashydrogen fluoride absorbents.

[0076] 1. Activated Alumina A-202HF

[0077] Manufacturer: UOP, Des Plaines, Ill.

[0078] Ingredients:

[0079] Aluminum oxide (Al₂O₃, non-fibrous)<95%

[0080] Water<10%

[0081] 2. DD-450

[0082] Manufacturer: Alcoa World Chemicals

[0083] Ingredients:

[0084] Aluminum oxide (Al₂O₃)<92.5%

[0085] Sodium oxide (Na₂O)<0.35%

[0086] Silicon Dioxide (SiO₂)<0.015%

[0087] 3. HF-200

[0088] Manufacturer: Alcoa World Chemicals

[0089] Ingredients:

[0090] Aluminum oxide (Al₂O₃)<94.9%

[0091] Sodium oxide (Na₂O)<0.02%

[0092] Ferric oxide (Fe₂O₃)<0.02%

[0093] Silicon Dioxide (SiO₂)<0.3%

[0094] 4. Florocel, Activated Alumina

[0095] Manufacturer: Lawrence Industries, UK

[0096] 5. Fluorocel 830,

[0097] Manufacturer: Porocel, AR

[0098] Ingredients:

[0099] Aluminum oxide (Al₂O₃)+Promoter<99.6%

[0100] Sodium oxide (Na₂O)<0.36%

[0101] Silicon Dioxide (SiO₂)<0.015%

[0102] 6. Actiguard HF

[0103] Manufacturer: Alcan Chemicals, TX & CO

[0104] Ingredients:

[0105] Aluminum oxide (Al₂O₃)<94.9%

[0106] Sodium oxide (Na₂O)<0.45%

[0107] Ferric oxide (Fe₂O₃)<0.015%

[0108] Silicon Dioxide (SiO₂)<0.02%

[0109] In addition to the materials listed above other commerciallyavailable materials which might be particularly useful as hydrogenchloride absorbents may also be included. It is noted that there is someoverlap with respect to the composition of these different reactantscavengers. More specifically, there is some overlap such as theinclusion of aluminum oxide in the hydrogen chloride absorbents withaluminum oxide also being present in the hydrogen fluoride absorbents.

[0110] 1. Activated alumina 9139A

[0111] Manufacturer: UOP, Des Plaines, Ill.

[0112] Ingredients:

[0113] Aluminum oxide (Al₂O₃, non-fibrous)<95%

[0114] Sodium oxide (Na₂O)<10%

[0115] Water<10%

[0116] 2. CL-750

[0117] Manufacturer: Alcoa World Chemicals

[0118] Ingredients:

[0119] Aluminum oxide (Al₂O₃)+Surface Modifier<95%

[0120] Sodium oxide (Na₂O)<0.37%

[0121] Silicon Dioxide (SiO₂)<0.015%

[0122] 3. Selexsorb® HCl

[0123] Manufacturer: Alcoa World Chemicals

[0124] Ingredients:

[0125] Aluminum oxide (Al₂O₃)+Surface Modifier<95.1%

[0126] Sodium oxide (Na₂O)<0.3%

[0127] Silicon Dioxide (SiO₂)<0.02%

[0128] Ferric oxide (Fe₂O₃)<0.02%

[0129] Another form of the reactant scavenger is an oxygen absorbent.Although there are a large number of different possible oxygenabsorbents the following commercially available materials might be foundto be particularly useful in connection with the present invention.

[0130] 3. Freshpax

[0131] Manufacturer: Multisorb Technologies, NY

[0132] Ingredients:

[0133] Iron Powder (50-60%)

[0134] Amorphous Silica (15-25%)

[0135] Water & NaCl (20-30%)

[0136] 4. Mitsubishi Ageless Oxygen Adsorbents

[0137] Ingredients:

[0138] Iron Powder

[0139] While the use of oxygen scavengers has been reported elsewhere inthe literature, the novel teaching of this invention include usingscavengers for the specific reactive species generated by irradiation ofthe polymer under consideration. Many of the scavengers described abovemay absorb other species than HF, HCl and oxygen and therefore may beutilized for practicing this invention by absorbing those species ifgenerated during irradiation. Furthermore, this invention also teachesthe art of combining the advantages of oxygen scavenging previouslyknown, with advantages of scavenger the reactive species formed duringirradiation as taught herein.

[0140] Composition of Polymeric Components

[0141] A wide range of different polymeric materials may be used inproducing the polymeric components of the invention. In general, thesematerials are widely known by those skilled in the art.

[0142] Typical examples of the polyolefin which can be used to form theoxygen absorbing layer 2 include polyethylenes such as low-densitypolyethylenes, straight-chain low-density polyethylenes, medium-densitypolyethylenes, high-density polyethylenes and metallocene polyethylenes(and copolymers), polypropylenes such as polypropylene,propylene-ethylene random copolymers, propylene-ethylene blockcopolymers and metallocene polypropylenes (and copolymers), polyolefinssuch as polymethylpentene (and copolymers), elastomers such asethylene-propylene rubbers, ethylene-vinyl acetate copolymers andmixtures thereof. In the case where the oxygen absorbing packagingcontainer is subjected to a retort treatment or a high retort treatment,the polyolefin to be used in the oxygen absorbing layer 2 has preferablya melting point of 135.degree. C. or higher. With regard to acombination of the resins which can be used to form the oxygenpermeating layer 1 and the oxygen absorbing layer 2, it is preferable toselect the same resin or different kinds of resins which are compatiblewith each other and which can thermally fuse each other.

Specific Embodiments

[0143]FIG. 1 is a schematic view of the embodiments of the invention.Specifically, FIG. 1 shows an outer package 1 which may be in the formof a plastic bag comprised of one or more polymer materials whichmaterials are substantially impermeable to inert gas which may bepresent inside the package 1 and contaminants which may be presentoutside the package 1. The package holds the polymer component 2 whichhere is in the form of laminated film (100-1500 ft) mounted on a plasticspool. The polymer component in the form of a tape 2 may be wound aroundthe polymer spool 3. The spool 3 includes oval shaped openings 7 and 9.Single or multiple openings of any shape may be used. The roll of filmmay be in the form of a plurality of separate components orsubcomponents. The components may be polymeric containers forpharmaceuticals. The components may be used as nozzles for aerosolizeddelivery of drugs. Examples of containers and nozzles are disclosed anddescribed in U.S. Pat. Nos. 5,709,202; 5,497,763; 5,544,646; 5,718,222;and 6,123,068 and related patents all of which are incorporated hereinby reference in their entirety and to disclose container and nozzlecomponents specifically.

[0144] In one embodiment the polymer component 2 has a plurality ofpackets such as the packets 4 and 5 attached to its surface. The packets4 and 5 can contain one or more reactant scavengers such as aluminumoxide, sodium oxide, silicon dioxide, ferric oxide and the like. Thepurpose of the reactant scavengers is to render non-reactive componentssuch as hydrogen chloride, hydrogen fluoride and oxygen. The reactantscavengers can be embedded into the polymer component 2 or embedded intovarious components of the polymer component 2 which components may beone or more subcomponents which are smaller than the overall component2.

[0145] Packets of reactant absorbents such as oxygen adsorbent packages6 and 8 are placed in this position for convenience near the holes 7 and9 but in practicality they could be placed anywhere inside the container1. Individual polymer components such as the polymer component may bepresent by themselves or present in the package 1 along with the largerpolymeric component 2.

[0146] It will be understood by those skilled in the art that thepolymer components may have adhesives thereon and may be in any size orshape and further that the polymer component may be comprised of one,two, or a plurality of different polymers so as to obtain the desiredresult.

[0147] The package 1 containing the polymer components such as thepolymer component 2 can be placed in additional packages or placed inthe box and shipped for sterilizing radiation. Accordingly, the package1 must be comprised of a material which can be permeated by thesterilizing radiation. Further, the material making up the package 1preferably has sufficient structural integrity that it does not breakduring shipping to the point where it is sterilized or break in returnshipment or during storage.

EXAMPLES

[0148] The following examples are put forth so as to provide those ofordinary skill in the art with a complete disclosure and description ofhow to make and use the present invention, and are not intended to limitthe scope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

Example 1

[0149] A blister film laminate comprising of polychlorotrifluoroethylene(PCTFE) and ethylene acrylic acid (EAA) was tested by exposure to gammairradiation dose of 25-35 kGy in air and by using an inert environmentand a HF, HCl scavenger-based process. Irradiation of such laminatestuctures results in formation of F⁻ & Cl⁻ based reactive species thatcontinue to degrade the film stored inside a sealed container duringpost-irradiation shelf life.

[0150] The sterilization packages was made by placing the roll ofblister film laminate (300-1200 ft) mounted on a reel in threepolyethylene bags (20′×20′) and then heat-sealing all three bags. In thecontrol condition no scavengers were placed and the environment insidethe triple-bagged package was ambient. The inert environment for gammaprocessing was created by using oxygen and HF/HCl adsorbents as follows:

[0151] Oxygen Adsorbent:

[0152] Freshpax Type D-500. Manufacturer: Multisorb Technologies, NYEach packet is capable of adsorbing 500 cc of oxygen. Two of thesepackets were used to irradiate 1000 ft of film and the two packets weretaped to the side of the reel that contained the roll of film.

[0153] HF & HCl Adsorbents:

[0154] HF:Activated Alumina A-202HF. Manufacturer: UOP, Des Plaines,Ill.

[0155] HCl: Activated alumina 9139A. Manufacturer: UOP, Des Plaines,Ill.

[0156] Approx. 10±/−2 g of these adsorbents was placed in VWR brandCritical Cover Tyvek Sterility Pouches (2 in.×3 in.) and heat-sealed.The pouches were taped circumferentially around the roll of blister filmin alternating fashion. The number of packages used depended on size ofthe roll and for 800-1200 ft rolls eight (four each) pouches were used.

[0157] Nitrogen Flush:

[0158] In some cases a nitrogen flush was also used in the innermost bagalong with the scavengers before sealing the package.

[0159] These sterilization packages were sent for gamma irradiation toSterigenics, Hayward, CA, where they were irradiated to a dose range of25-35 kGy. After returning from the sterlization facility the rolls wereopened on predetermined days representing varying post gamma shelf livesfrom 3-12 weeks. The films were then tested for physical properties suchas tensile strength, toughness and peel strength in dry andwater-immersed conditions. It was found that the inert scavenger-basedprocess reduced changes in physical properties relative to the sameprocess without the reactant scavengers. Specifically, it was found thatthe invention reduced loss of tensile strength by 15-20%, toughness by30-40% and peel strength by 60-70% relative to a process withoutreactant scavengers. One of the most significant observations was thatadverse effects of the delamination rate of the film in variousstability conditions improved significantly as compared to the processwithout scavengers. It was concluded that the new process could be usedto increase the post-irradiated shelf life of these raw materials by asignificant length of time with a significant decrease in the loss ofphysical properties relative to a process without reactant scavengers.

[0160] While the present invention has been described with reference tothe specific embodiments thereof, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A method, comprising the steps of: sealing apolymeric component, an inert gas and reactant scavenger into acontainer impermeable to bacteria and the inert gas; irradiating thepolymer component and the container with radiation; and storing thecontainer in a manner such that the reactant scavenger in the containeris allowed to contact reactants formed during irradiation.
 2. The methodof claim 1, wherein the polymeric component is comprised of a materialchosen from olefin, polyolefin, vinyl polymer, polyether, polyester,polyamide, halogenated polymer, polysiloxane, ionic polymer,polyurethane, acrylic, cellulose, tannin, polysaccharide, and starch. 3.The method of claim 1, wherein the polymeric component is an olefinchosen from PE, PP, EMA, EVA and EAA.
 4. The method of claim 1, whereinthe polymeric component is a halogenated polymer chosen from PTFE,PCTFE, PVDF and PVC.
 5. The method of claim 1, wherein the reactantscavenger is chosen from aluminum oxide, sodium oxide, silicon dioxideand ferric oxide.
 6. The method of claim 1, wherein the inert gas ischosen from nitrogen, argon, helium, neon, xenon, and krypton.
 7. Themethod of claim 1, wherein the radiation is chosen from gammairradiation, x-ray irradiation, ultraviolet (UV) irradiation andelectron beam irradiation and the storing is over a period of three daysor more.
 8. The method of claim 1, wherein artificially createdradiation is chosen from gamma radiation, X-rays, UV, and e-beamradiation for sterilization purposes in an amount in a range of fromabout 25 to about 35 kGy and the storing is over a period of seven daysof more.
 9. The method of claim 1, wherein the reactants are chosen fromHCl, HF, HBr and HI and the storing is over a period of thirty days ormore.
 10. The method of claim 1, wherein the reactant scavengercomprises an acid adsorbent and physical properties of the polymercomponent are stabilized in a range of ±25% over a period of thirtydays.
 11. The method of claim 1, wherein the container is stored for oneweek or more following the irradiating.
 12. A packaged, sterilizedpolymeric component, comprising a polymeric component; an inert gas; areactant scavenger; and a sealed container holding the polymericcomponent, inert gas and reactant scavenger, the sealed container beingimpermeable to bacteria and the inert gas.
 13. The packaged, sterilizedpolymeric component of claim 12, wherein the polymeric component iscomprised of a material chosen from olefin, polyolefin, vinyl polymer,polyether, polyester, polyamide, halogenated polymer, polysiloxane,ionic polymer, polyurethane, acrylic, cellulose, tannin, polysaccharide,and starch.
 14. The packaged, sterilized polymeric component of claim12, wherein the polymeric component is an olefin chosen from PE, PP,EMA, EVA and EAA.
 15. The packaged, sterilized polymeric component ofclaim 12, wherein the polymeric component is a halogenated polymerchosen from PTFE, PCTFE, PVDF and PVC.
 16. The packaged, sterilizedpolymeric component of claim 12, wherein the reactant scavenger ischosen from aluminum oxide, sodium oxide, silicon dioxide and ferricoxide.
 17. The packaged, sterilized polymeric component of claim 12,wherein the inert gas is chosen from nitrogen, argon, helium, neon,xenon, and krypton.
 18. The packaged, sterilized polymeric component ofclaim 12, wherein the component is comprised of a plurality of differentpolymers.
 19. The packaged, sterilized polymeric component of claim 12,wherein the component is comprised of an adhesive.
 20. The packaged,sterilized polymeric component of claim 12, wherein the reactantscavenger is in one or more packets attached to the polymer component.21. The packaged, sterilized polymeric component of claim 12, whereinthe reactant scavenger is embedded in the polymer component.
 22. Thepackaged, sterilized polymeric component of claim 12, wherein thepolymer component is comprised of a main component and a smallersubcomponent which has embedded therein the reactant scavenger.